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The tumor necrosis factor (TNF) inhibitor certolizumab pegol (Cimzia) appears to significantly increase the survival rate for pregnancies complicated by antiphospholipid syndrome (APS), an autoimmune thrombo-inflammatory disorder, when added to standard therapy with low-molecular-weight heparin (LMWH) and low-dose aspirin (LDA), according to results from the first trial of its kind.

In the IMPACT trial, treatment with certolizumab led to an 18% rate of adverse pregnancy outcomes, compared with rates of 44% in similar patients from a previous research study who met participation criteria and 37% in those patients who were taking LMWH and LDA, Jane Salmon, MD, of Hospital for Special Surgery (HSS), New York City, and coauthors reported on April 10, 2025, in Annals of the Rheumatic Diseases.

The placental-mediated adverse pregnancy outcomes defined by the single-arm open-label, phase 2 trial were otherwise unexplained fetal death ≥ 10 weeks’ gestation or preeclampsia with severe features or placental insufficiency requiring delivery before 34 weeks’ gestation.

The average gestational age at delivery was 36.5 weeks in certolizumab-treated pregnancies of patients with APS compared with 24 weeks for prior pregnancies of patients participating in IMPACT, said Salmon, a physician-researcher who specializes in lupus and other autoimmune diseases at HSS. [Editor’s note: Read a related Q&A with Salmon about IMPACT at the end of this article.]

The IMPACT study called for administration of certolizumab 400 mg subcutaneously beginning by 8 weeks and 6 days of gestation, 400 mg at 2 and 4 weeks later, and 200 mg every other week until 28 weeks’ gestation. Each patient also received LMWH (at either therapeutic or thromboprophylactic doses) plus LDA under the supervision of their physician. A total of 61% were also receiving hydroxychloroquine at enrollment.

The trial enrolled 51 pregnant patients in the United States and Canada with APS and lupus anticoagulant as an intention-to-treat population, losing six participants later from analysis because of a pregnancy loss at < 10 weeks’ gestation and fetal deaths due to genetic abnormalities. A total of 10 patients had systemic lupus erythematosus.

The researchers reported that 93% of participants included in a modified intention-to-treat analysis completed their pregnancies with live births and brought their infants home. That compares with a 38% survival rate for their previous pregnancies while taking only LMWH and LDA.

Patrick Schneider, MD, assistant professor and medical director for inpatient obstetrics at The Ohio State University Wexner Medical Center, Columbus, Ohio, who was not involved with this research, said the trial’s findings reinforce the need to check for APS after women experience stillbirth, although this is a rare condition. 

“I always try to remind my residents when I’m teaching them that this is one of the most crucial tests that you can do. And even though it’s not likely to come back positive, if it does, you have potentially a modifiable element to manage this condition,” Schneider said.

Salmon and coauthors made a convincing case for designing IMPACT as a single-arm intervention study, Schneider said.

“There are always going to be strengths and weaknesses of different studies. Ideally, it would be great if we could have the gold standard, double-blind, randomized controlled trial, but that’s just not really practical in this particular patient population,” Schneider said.

“We already have a pretty good compendium of understanding of the kind of the outcomes for these patients,” in terms of their use of aspirin and LMWH to try to prevent adverse pregnancy outcomes, he added.

‘Cultural Change’ 

IMPACT was the first clinical trial to evaluate biologic therapy to prevent serious adverse outcomes in pregnant patients, Salmon and coauthors wrote. 

It’s part of broader efforts to study how medical treatments affect both pregnant patients and fetuses. 

For many decades, researchers have steered away from enrolling pregnant patients in clinical trials, resulting in a dearth of information about drugs and treatments in these patients. This reluctance was due in part to concerns raised by the early 1960s cases of thalidomide-linked birth defects, according to a 2024 National Academies of Sciences, Engineering, and Medicine (NASEM) report.

Yet about 70% of pregnant patients take one or more prescription medications, often related to nonobstetric conditions, the NASEM report said. NASEM urged the US Food and Drug Administration (FDA) to encourage companies to design clinical trials to allow safe enrollment of pregnant patients. 

In 1977, the FDA issued guidance recommending against including women of childbearing potential in early phases of clinical research. But in recent years, the FDA has sought to identify ways in which pregnant patients may be safely enrolled in studies. It held a workshop in 2021 addressing this issue. 

The aim was to change the “default response” against enrolling pregnant patients in trials, FDA staff wrote in a 2021 website post about the workshop. 

“Pregnant patients may not be included in clinical studies for scientific, legal, logistical, and financial reasons. But these reasons do not apply to every clinical study,” the FDA staff wrote. “At the beginning of each research endeavor, we need to consider if and how to enroll pregnant patients as safely as possible.”

“The cultural change may be our most daunting task,” the staff added.

The American College of Obstetricians and Gynecologists (ACOG) also has urged changes in clinical trials to allow more pregnant patients to participate.

In a 2024 statement, ACOG said there’s “an ethical imperative” to increase participation in clinical research by people who can become pregnant, who are pregnant, and who are lactating, because this will improve maternal and fetal health.

“The risk status for pregnant people and fetuses is unknown for the vast majority of FDA-approved medications. Had these drugs been studied in pregnancy early in their use, data on risk may have provided an opportunity to better balance the risks and benefits of their use,” ACOG said in the statement. 

Louise P. King, MD, JD, director of reproductive bioethics at the Center for Bioethics at Harvard Medical School, helped develop ACOG’s 2024 statement regarding inclusion of more pregnant patients in clinical trials. 

She told Medscape Medical News that companies have incentive to try to skew enrollment in clinical trials toward men because it makes this research both less risky and somewhat easier to manage.

“It makes everything more complicated the more diverse your population is,” said King, who is also a surgeon in the Division of Minimally Invasive Gynecologic Surgery at Brigham and Women’s Hospital. 

The ACOG statement was intended to encourage drugmakers and scientists involved with clinical research to take on the challenges of enrolling more pregnant patients, King said.

“The onus is really on the researchers and the companies to ensure that we include people, [and] that we educate people so that they can make good, informed decisions about whether to participate” in clinical trials while pregnant, she said.

Q&A With Jane Salmon on the IMPACT Trial

Medscape Medical News spoke with Salmon about the uniqueness of the IMPACT trial and the tenacity of its participants, supporters, and investigators in seeing it to completion.

Before proceeding to this trial, Salmon and colleagues completed an observational study of 775 pregnancies to determine the strongest predictors of pregnancy complications in patients with lupus and/or APS. They found that the presence of certain autoantibodies in women with APS with or without lupus was associated with a nearly 50% risk for serious adverse pregnancy outcomes and established a model to predict risk for adverse outcomes in pregnant persons with APS.

Tell us how your earlier lab research with mice set the stage for the IMPACT trial.

Historically, it was believed clotting caused the pregnancy problem. APS is associated with thromboses in arteries and veins, so why not the placenta? Patients with APS are treated with aspirin and LMWH during pregnancy, but it’s not very effective. We still see a high rate of adverse pregnancy outcomes. In our experimental mouse models, we discovered that inflammation was necessary and sufficient for pregnancy complications. 

I can’t say clotting is irrelevant, but inflammation is very important. We defined the specific inflammatory pathways that mediate injury at the maternal-fetal interface and discovered that TNF blockade rescued pregnancies in pregnant mice treated with human APS — the autoantibodies that cause pregnancy complications in patients. 

The ability to use our risk stratification algorithm to identify risky pregnancies in APS, taken together with the mouse studies, allowed us to design a study to test the hypothesis that the addition of a TNF blocker to standard of care therapy would improve pregnancy outcomes.

How did you decide on certolizumab as the study drug? What were the next steps?

There are many TNF blockers, but certolizumab is unique: Because of its structure, it doesn’t cross the placenta and enter the fetus. Although TNF blockers have not been shown to be dangerous in pregnancy, this one made us most comfortable.

Despite the historic challenges of trials in pregnant people who were considered a vulnerable population excluded for research, we obtained approval from the FDA and our institutional review board. We believe this is the first trial of biologic therapy to prevent pregnancy complications. 

None of the 51 patients who completed the study were lost to follow-up. How unusual was that?

Patients in the IMPACT trial were part of our research team. We were in contact with them at least every 2 weeks through their pregnancies. Our study patients were very committed to the trial, as were our study coordinators. Most of the patients — 88% — had suffered severe complications in past pregnancies, such as preeclampsia and fetal deaths, and only 37% had a live birth survive to hospital discharge. Their most recent pregnancy before they were enrolled in our trial ended with an average gestational age of 24 weeks, whereas the average gestational age of pregnancies in these women in the IMPACT trial was 37 weeks. 94% of the patients brought home healthy babies. 

These women were anxious to enroll and accept the risk of taking a biologic therapy to protect their pregnancies. They were willing to be partners, to help themselves and to help others. A number of them wanted to have subsequent pregnancies but have had difficulties obtaining coverage for certolizumab. Some who were able to obtain the medication have had successful second pregnancies. We hope that publication of the IMPACT trial makes access to this promising therapy easier for the appropriate patients.

IMPACT was feasible and successful because it was a partnership between academia, the National Institutes of Health, foundations, and industry. We had support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Lupus Foundation of America, and an investigator-initiated grant from UCB (the manufacturer of certolizumab). These were bold to support our trial.

Tell me about the unusual approach to recruiting patients.

APS is uncommon, and APS patients at the highest risk for pregnancy are rare. It took 6 years to enroll 51 patients, using a rare disease trial approach. The co–principal investigator of IMPACT is Dr Ware Branch, a maternal-fetal medicine expert and professor of obstetrics and gynecology at the University of Utah in Salt Lake City. 

University of Utah has experience with remote consenting for interventional trials. We presented the study to conferences with experts in management of high-risk pregnancies and rheumatologists who cared for patients with APS and waited for them to refer complex APS patients to us. We ultimately enrolled patients from 18 states and one Canadian province.

Every patient was screened by Dr Branch and consented by a credentialed individual in his institution over the phone. Then my team at HSS would take over. We collected the clinical data from monthly obstetric visits, called the patients every 1-2 weeks to remind them to administer the study medication (which was an injection every 2 weeks) and assess their general health and side effects of the study medication. Patients sent their blood samples to HSS for analyses and future biomarker studies.

What didn’t go as well as you’d initially expected with the IMPACT trial?

The study was initially proposed to go for 3 years. We were unrealistic. It took a year to obtain all of the regulatory approvals. Then when enrollment began, it took time to inform our colleagues in rheumatology, hematology, and obstetrics and hematology about the trial. Once we gained momentum, the pandemic struck. 

Despite this, our patients stayed the course and new ones enrolled. The study took 6 years instead of 3 years. That’s a long time, but it was worth the wait.

The IMPACT trial was supported by funding from the National Institutes of Health, the Lupus Foundation of America, the Morris and Alma Schapiro Fund, the James R. and Jo Scott Research Endowment at the University of Utah, and UCB. Salmon reported receiving funding grants from the Morris and Alma Schapiro Fund and Lupus Foundation of America; serving as a board member and performing consulting or advisory work with UCB; receiving speaking and lecture fees from Washington University, St. Louis, Atkinson Lecture; and holding equity or stocks in Pfizer, Johnson & Johnson, Bristol Myers Squibb, Biogen, and Eli Lilly. Schneider and King had no relevant financial disclosures. 

Kerry Dooley Young is a freelance journalist based in Washington, DC. She has reported on medical research and healthcare policy for more than 25 years.